Abstract
Cancer cells breach the endothelium not only through cell-cell junctions but also via individual endothelial cells (ECs), or transcellular invasion. The underlying EC forms a circular structure around the transcellular invasion pore that is dependent on myosin light chain kinase (MLCK) and myosin II regulatory light chain (RLC) phosphorylation. Here we offer mechanistic insights into transcellular invasive array formation amid persistent tensile force from activated EC myosin. Fluorescence recovery after photobleaching (FRAP) experiments, sarcomeric distance measurements using super-resolution microscopy and electron microscopy provide details about the nature of the myosin II invasion array. To probe the relationship between biomechanical forces and the tension required to maintain the curvature of contractile filaments, we targeted individual actin-myosin fibers at the invasion site for photoablation. We showed that adjacent filaments rapidly replace the ablat11ed structures. We propose that the transcellular circumferential invasion array (TCIA) provides the necessary constraint within the EC to blunt the radial compression from the invading cancer cell.
Highlights
The entry of cancer cells into the bloodstream is a critical point in the metastatic cascade [1] and usually leads to poor prognosis [2,3]
We hypothesize that the transcellular circumferential invasion array (TCIA) forms as a reaction to forces generated by the invading cancer cell
We did not observe similar repositioning of adjacent fiber when stress fibers were ablated in resting endothelial cells (ECs) (Figure 5, C and F; Movie S5). Transendothelial migration of both cancer cell and leukocytes can be mechanistically divided into three distinct stages as defined by the response of the underlying endothelium
Summary
The entry of cancer cells into the bloodstream is a critical point in the metastatic cascade [1] and usually leads to poor prognosis [2,3]. Transcellular migration is not restricted to tumor invasion and occurs frequently in leukocyte diapedesis. Both leukocyte and cancer transcellular migration share parallel features, implicating the presence of a potentially conserved mechanism within the EC. As transcellular migration proceeds to the active phase, the EC cytoskeleton begins to reorganize and form transient structures that encapsulate the intrusive cell [8,14]. These events provide clues about the signaling crosstalk between the transmigrating cell and the EC that converge on cytoskeletal and membranous networks
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